Alois Alzheimer first reported the extraordinarily strong accumulation of lipid material in the ganglion cells, glia, and vascular wall cells in the human brain of demented patients. In conjunction, prenatal alcohol exposure also mediated significant lipid accumulation in the frontal cortex of the brain. The underlying pathophysiology of these events involves mainly the glycerophospholipids like lysophosphatidic acid (LPA), a well-known participant in atherosclerotic disease. However, its role in prenatal alcohol-mediated cerebral lipid dysfunction remains virtually unexplored. LPA production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes LPA dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that prenatal alcohol exposure enhances the cerebrovascular autotaxin levels and decreases LPP3 expression, leading to increased LPA signaling. Upon prenatal alcohol exposure, the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) has been shown to bind to the autotaxin promoter and induce its expression. Furthermore, prenatal alcohol exposure induced oxidative stress transactivates microRNA-92a, which act as a negative regulator of LPP3. Increased autotaxin expression found in the frontal cortex of Alzheimer?s patients suggests that altered lysophosphatidic acid metabolism might contribute to the pathology of the disease. Recent studies have shown a positive correlation between cerebrospinal fluid (CSF) levels of ?- amyloid (A?), and oxLDL derived LPA increase in Alzheimer disease, but the question remains about the LPA regulatory enzymes. The following interrelated specific aims will provide a step-wise and in-depth study using in vitro, in vivo, and experimental therapeutics approach. Specific aim 1 will assess the role of autotaxin expression and Alzheimer?s disease progression following prenatal alcohol exposure. Specific aim 2 will determine the role of LPP3 depletion and Alzheimer?s disease progression following prenatal alcohol exposure. We could identify whether modulation of autotaxin and LPP3 confers a differential protective effect following prenatal alcohol exposure and in Alzheimer disease risk. Our results should provide specific insight into the signaling system mediated by prenatal alcohol exposure and may reveal novel targets for treatment and might improve cerebrovascular disorders.